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Warren G. Young

Bio: Warren G. Young is an academic researcher from Scripps Research Institute. The author has contributed to research in topics: Hippocampal formation & Dentate gyrus. The author has an hindex of 18, co-authored 26 publications receiving 1946 citations. Previous affiliations of Warren G. Young include Torrey Pines Institute for Molecular Studies & Scripps Health.

Papers
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Journal ArticleDOI
TL;DR: In this paper, the authors performed comprehensive gene expression mapping of the 11 HDAC isoforms (HDAC1-11) (classes I, II, and IV) throughout the rat brain using high-resolution in situ hybridization (ISH) and imaging technology.
Abstract: Although protein phosphorylation has been characterized more extensively, modulation of the acetylation state of signaling molecules is now being recognized as a key means of signal transduction. The enzymes responsible for mediating these changes include histone acetyl transferases and histone deacetylases (HDACs). Members of the HDAC family of enzymes have been identified as potential therapeutic targets for diseases ranging from cancer to ischemia and neurode generation. We initiated a project to conduct comprehensive gene expression mapping of the 11 HDAC isoforms (HDAC1-11) (classes I, II, and IV) throughout the rat brain using high-resolution in situ hybridization (ISH) and imaging technology. Internal and external data bases were employed to identify the appropriate rat sequence information for probe selection. In addition, immunohistochemistry was performed on these samples to separately examine HDAC expression in neurons, astrocytes, oligodendrocytes, and endothelial cells in the CNS. This double-labeling approach enabled the identification of specific cell types in which the individual HDACs were expressed. The signals obtained by ISH were compared to radiolabeled standards and thereby enabled semiquantitative analysis of individual HDAC isoforms and defined relative levels of gene expression in >50 brain regions. This project produced an extensive atlas of 11 HDAC isoforms throughout the rat brain, including cell type localization, providing a valuable resource for examining the roles of specific HDACs in the brain and the development of future modulators of HDAC activity.

334 citations

Journal ArticleDOI
TL;DR: It is concluded that overexpression of APP and amyloid may initiate pathologic changes before the appearance of plaques, suggesting novel targets for the treatment of Alzheimer's disease and further reinforcing the need for early diagnosis and treatment.
Abstract: High-resolution magnetic resonance microscopy (MRM) was used to determine regional brain volumetric changes in a mouse model of Alzheimer's disease. These transgenic (Tg) mice overexpress human mutant amyloid precursor protein (APP) V717F under control of platelet-derived growth factor promoter (PDAPP mice), and cortical and hippocampal beta-amyloid (Abeta) deposits accumulate in heterozygotes after 8-10 mos. We used MRM to obtain 3D volumetric data on mouse brains imaged in their skulls to define genotype- and age-related changes. Hippocampal, cerebellar, and brain volumes and corpus callosum length were quantified in 40-, 100-, 365-, and 630-day-old mice. Measurements taken at age 100 days, before A(beta) deposition, revealed a 12.3% reduction of hippocampus volume in Tg mice compared with WT controls. This reduction persisted without progression to age 21 mos. A significant 18% increase in hippocampal volume occurred between 40 and 630 days in WT mice, and no corresponding significant increase occurred in Tg mice. Cavalieri volume estimates of hippocampal subfields from 100-day-old Tg mice further localized a 28% volume deficit in the dentate gyrus. In addition, corpus callosum length was reduced by approximate to 25% in Tg mice at all ages analyzed. In summary, reduced hippocampal volume and corpus callosum length can be detected by MIRM before Abeta deposition. We conclude that overexpression of APP and amyloid may initiate pathologic changes before the appearance of plaques, suggesting novel targets for the treatment of Alzheimer's disease and further reinforcing the need for early diagnosis and treatment.

203 citations

Journal ArticleDOI
TL;DR: A gene expression-based brain map measuring gene expression patterns for 24 neural tissues covering the mouse central nervous system found that the adult brain bears a transcriptional "imprint" consistent with both embryological origins and classic evolutionary relationships.
Abstract: The current model to explain the organization of the mammalian nervous system is based on studies of anatomy, embryology, and evolution. To further investigate the molecular organization of the adult mammalian brain, we have built a gene expression-based brain map. We measured gene expression patterns for 24 neural tissues covering the mouse central nervous system and found, surprisingly, that the adult brain bears a transcriptional "imprint" consistent with both embryological origins and classic evolutionary relationships. Embryonic cellular position along the anterior-posterior axis of the neural tube was shown to be closely associated with, and possibly a determinant of, the gene expression patterns in adult structures. We also observed a significant number of embryonic patterning and homeobox genes with region-specific expression in the adult nervous system. The relationships between global expression patterns for different anatomical regions and the nature of the observed region-specific genes suggest that the adult brain retains a degree of overall gene expression established during embryogenesis that is important for regional specificity and the functional relationships between regions in the adult. The complete collection of extensively annotated gene expression data along with data mining and visualization tools have been made available on a publicly accessible web site (www.barlow-lockhart-brainmapnimhgrant.org).

185 citations

Journal ArticleDOI
TL;DR: The results suggest that paravalbumin-immunoreactive cells represent a neuronal subset resistant to degeneration, and further support the hypothesis that the pathological process in Alzheimer's disease involves specific neuronal subtypes with particular morphological and molecular characteristics.
Abstract: Recent studies have stressed the fact that specific neuronal subtypes may display a differential sensitivity to degeneration in Alzheimer's disease. For example, large pyramidal neurons have been shown to be vulnerable, whereas smaller neurons are resistant to pathology. Using a monoclonal antibody against the calcium-binding protein parvalbumin, we investigated the possible changes in a subpopulation of interneurons in two cortical areas known to be strongly damaged in Alzheimer's disease. In the prefrontal cortex as well as in the inferior temporal cortex, we observed no differences in parvalbumin-immunoreactive cell counts or cell size in Alzheimer's disease brains as compared to control cases. Moreover, the general cellular morphology of these neurons was preserved in the Alzheimer's disease cases, in that their perikarya and dendritic arborizations were intact. These results suggest that paravalbumin-immunoreactive cells represent a neuronal subset resistant to degeneration, and further support the hypothesis that the pathological process in Alzheimer's disease involves specific neuronal subtypes with particular morphological and molecular characteristics.

175 citations

Journal ArticleDOI
TL;DR: The neuroanatomical distribution of amyloid-beta-protein mRNA within neuronal subpopulations of the hippocampal formation in the cynomolgus monkey, normal aged human, and patients with Alzheimer disease is mapped.
Abstract: We have mapped the neuroanatomical distribution of amyloid-beta-protein mRNA within neuronal subpopulations of the hippocampal formation in the cynomolgus monkey (Macaca fascicularis), normal aged human, and patients with Alzheimer disease. Amyloid-beta-protein mRNA appears to be expressed in all hippocampal neurons, but at different levels of abundance. In the central nervous system of monkey and normal aged human, image analysis shows that neurons of the dentate gyrus and cornu Ammonis fields contain a 2.5-times-greater hybridization signal than is present in neurons of the subiculum and entorhinal cortex. In contrast, in the Alzheimer disease hippocampal formation, the levels of amyloid-beta-protein mRNA in the cornu Ammonis field 3 and parasubiculum are equivalent. These findings suggest that within certain neuronal subpopulations cell type-specific regulation of amyloid-beta-protein gene expression may be altered in Alzheimer disease.

166 citations


Cited by
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Journal ArticleDOI
Ed S. Lein1, Michael Hawrylycz1, Nancy Ao2, Mikael Ayres1, Amy Bensinger1, Amy Bernard1, Andrew F. Boe1, Mark S. Boguski3, Mark S. Boguski1, Kevin S. Brockway1, Emi J. Byrnes1, Lin Chen1, Li Chen2, Tsuey-Ming Chen2, Mei Chi Chin1, Jimmy Chong1, Brian E. Crook1, Aneta Czaplinska2, Chinh Dang1, Suvro Datta1, Nick Dee1, Aimee L. Desaki1, Tsega Desta1, Ellen Diep1, Tim A. Dolbeare1, Matthew J. Donelan1, Hong-Wei Dong1, Jennifer G. Dougherty1, Ben J. Duncan1, Amanda Ebbert1, Gregor Eichele4, Lili K. Estin1, Casey Faber1, Benjamin A.C. Facer1, Rick Fields2, Shanna R. Fischer1, Tim P. Fliss1, Cliff Frensley1, Sabrina N. Gates1, Katie J. Glattfelder1, Kevin R. Halverson1, Matthew R. Hart1, John G. Hohmann1, Maureen P. Howell1, Darren P. Jeung1, Rebecca A. Johnson1, Patrick T. Karr1, Reena Kawal1, Jolene Kidney1, Rachel H. Knapik1, Chihchau L. Kuan1, James H. Lake1, Annabel R. Laramee1, Kirk D. Larsen1, Christopher Lau1, Tracy Lemon1, Agnes J. Liang2, Ying Liu2, Lon T. Luong1, Jesse Michaels1, Judith J. Morgan1, Rebecca J. Morgan1, Marty Mortrud1, Nerick Mosqueda1, Lydia Ng1, Randy Ng1, Geralyn J. Orta1, Caroline C. Overly1, Tu H. Pak1, Sheana Parry1, Sayan Dev Pathak1, Owen C. Pearson1, Ralph B. Puchalski1, Zackery L. Riley1, Hannah R. Rockett1, Stephen A. Rowland1, Joshua J. Royall1, Marcos J. Ruiz2, Nadia R. Sarno1, Katherine Schaffnit1, Nadiya V. Shapovalova1, Taz Sivisay1, Clifford R. Slaughterbeck1, Simon Smith1, Kimberly A. Smith1, Bryan I. Smith1, Andy J. Sodt1, Nick N. Stewart1, Kenda-Ruth Stumpf1, Susan M. Sunkin1, Madhavi Sutram1, Angelene Tam2, Carey D. Teemer1, Christina Thaller2, Carol L. Thompson1, Lee R. Varnam1, Axel Visel5, Axel Visel4, Ray M. Whitlock1, Paul Wohnoutka1, Crissa K. Wolkey1, Victoria Y. Wong1, Matthew J.A. Wood2, Murat B. Yaylaoglu2, Rob Young1, Brian L. Youngstrom1, Xu Feng Yuan1, Bin Zhang2, Theresa A. Zwingman1, Allan R. Jones1 
11 Jan 2007-Nature
TL;DR: An anatomically comprehensive digital atlas containing the expression patterns of ∼20,000 genes in the adult mouse brain is described, providing an open, primary data resource for a wide variety of further studies concerning brain organization and function.
Abstract: Molecular approaches to understanding the functional circuitry of the nervous system promise new insights into the relationship between genes, brain and behaviour. The cellular diversity of the brain necessitates a cellular resolution approach towards understanding the functional genomics of the nervous system. We describe here an anatomically comprehensive digital atlas containing the expression patterns of approximately 20,000 genes in the adult mouse brain. Data were generated using automated high-throughput procedures for in situ hybridization and data acquisition, and are publicly accessible online. Newly developed image-based informatics tools allow global genome-scale structural analysis and cross-correlation, as well as identification of regionally enriched genes. Unbiased fine-resolution analysis has identified highly specific cellular markers as well as extensive evidence of cellular heterogeneity not evident in classical neuroanatomical atlases. This highly standardized atlas provides an open, primary data resource for a wide variety of further studies concerning brain organization and function.

4,944 citations

Journal ArticleDOI
TL;DR: In this Review a model is developed to explain why different disorders emerge in individuals exposed to stress at different times in their lives.
Abstract: Chronic exposure to stress hormones, whether it occurs during the prenatal period, infancy, childhood, adolescence, adulthood or aging, has an impact on brain structures involved in cognition and mental health. However, the specific effects on the brain, behaviour and cognition emerge as a function of the timing and the duration of the exposure, and some also depend on the interaction between gene effects and previous exposure to environmental adversity. Advances in animal and human studies have made it possible to synthesize these findings, and in this Review a model is developed to explain why different disorders emerge in individuals exposed to stress at different times in their lives.

4,739 citations

Journal ArticleDOI
01 Apr 1991-Neuron
TL;DR: The salient features of the altered biochemistry of AD brain tissue and the possible role of these changes in the pathogenesis of this complex disease are reviewed here.

2,499 citations

Journal ArticleDOI
TL;DR: Accumulating evidence suggests that soluble forms of Aβ are indeed the proximate effectors of synapse loss and neuronal injury in Alzheimer’s disease.
Abstract: Converging lines of evidence suggest that progressive accumulation of the amyloid beta-protein (A beta) plays a central role in the genesis of Alzheimer's disease, but it was long assumed that A beta had to be assembled into extracellular amyloid fibrils to exert its cytotoxic effects. Over the past decade, data have emerged from the use of synthetic A beta peptides, cell culture models, beta-amyloid precursor protein transgenic mice and human brain to suggest that pre-fibrillar, diffusible assemblies of A beta are also deleterious. Although the precise molecular identity of these soluble toxins remains unsettled, accumulating evidence suggests that soluble forms of A beta are indeed the proximate effectors of synapse loss and neuronal injury. Here we review recent progress in understanding the role of soluble oligomers in Alzheimer's disease.

1,947 citations

Journal ArticleDOI
TL;DR: One possibility is that lifetime cerebral metabolism associated with regionally specific default activity predisposes cortical regions to AD-related changes, including amyloid deposition, metabolic disruption, and atrophy, which may be part of a network with the medial temporal lobe whose disruption contributes to memory impairment.
Abstract: Alzheimer's disease (AD) and antecedent factors associated with AD were explored using amyloid imaging and unbiased measures of longitudinal atrophy in combination with reanalysis of previous metabolic and functional studies. In total, data from 764 participants were compared across five in vivo imaging methods. Convergence of effects was seen in posterior cortical regions, including posterior cingulate, retrosplenial, and lateral parietal cortex. These regions were active in default states in young adults and also showed amyloid deposition in older adults with AD. At early stages of AD progression, prominent atrophy and metabolic abnormalities emerged in these posterior cortical regions; atrophy in medial temporal regions was also observed. Event-related functional magnetic resonance imaging studies further revealed that these cortical regions are active during successful memory retrieval in young adults. One possibility is that lifetime cerebral metabolism associated with regionally specific default activity predisposes cortical regions to AD-related changes, including amyloid deposition, metabolic disruption, and atrophy. These cortical regions may be part of a network with the medial temporal lobe whose disruption contributes to memory impairment.

1,927 citations